By STEPHANIE SAUL
An article released today by The New England Journal of Medicine raised safety questions about the widely-used diabetes pill Avandia. An analysis of clinical trials concluded that the drug might significantly increase the risk of heart attacks.
The Food and Drug Administration issued what it called a “safety alert” in response, advising patients who are taking Avandia, particularly those at high risk for a heart attack, to seek advice from their doctors.
The agency also said it had been evaluating a possible increased risk since last August and announced plans today to convene an advisory panel to review the issue as quickly as possible. But government regulators cautioned that they had not confirmed the significance of the findings.
The journal, a prestigious weekly, posted the paper on its Web site, ahead of its print publication June 14, a step the editors take with matters they consider to have public health importance.
The journal’s editor, Dr. Jeffrey M. Drazen, said: “We view this as the best publicly available data on a very important question. It shows what we regard as a preliminary, but worrisome, signal about cardiovascular toxicity of this drug.”
While noting possible weaknesses in data used in the analysis, an accompanying editorial calls for a Food and Drug Administration review and questions why physicians would prescribe Avandia, which is made by the British pharmaceutical company GlaxoSmithKline and known generically as rosiglitazone.
The study was inadvertently published prior to an embargo. It was not supposed to be released until 5 p.m., after the closing bell on Wall Street. The company’s stock fell more than 8 percent by midafternoon, after the article appeared.
GlaxoSmithKline issued a news release defending Avandia’s safety and saying it “strongly disagrees” with the conclusions of the journal article, which it said were based on incomplete evidence and a flawed methodology.
“The totality of the data show that Avandia has a comparable cardiovascular profile to other oral antidiabetic medicines,” the release said. “GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks.”
Avandia, on the market since 1999, is used by nearly two million people a year worldwide, including a million in the United States, for the treatment of Type 2, or adult-onset, diabetes. It is sold alone as Avandia and in combination with other drugs as Avandamet and Avandryl. With $3.2 billion in worldwide sales last year, it was Glaxo’s second-biggest product after the asthma inhalant Advair.
The editorial, by Dr. Bruce M. Psaty of the University of Washington and Dr. Curt Furberg of Wake Forest University, said the accompanying study had once again spotlighted flaws in the nation’s drug approval and monitoring system. They asserted that those problems had not been fully addressed by recently passed legislation meant to strengthen the agency’s powers.
Both Dr. Psaty and Dr. Furberg have been critical of the drug approval process in the past.
“In view of the potential cardiovascular risks,” the editorial said, “and in the absence of evidence of other related advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear.” The editorial cautioned patients not to stop taking the medication without discussing it with their doctors.
Dr. Drazen said patients concerned about the drug should meet with their doctors to decide whether to remain on it or switch to another drug.
The finding — that Avandia raises the risk of heart attack by 43 percent — was based on a review of 44 studies of the drug. The review was conducted by Dr. Steven E. Nissen and Kathy Wolski of the Cleveland Clinic, where Dr. Nissen is the chief of cardiovascular medicine.
Dr. Nissen was among the first doctors to raise questions about the cardiovascular safety of Vioxx, the Merck painkiller that was withdrawn from the market in 2004. His concerns about Avandia were first publicly raised last December in a letter in the Lancet.
Dr. Nissen’s letter noted increased cardiovascular problems in a 5,000-patient clinical study, called Dream. GlaxoSmithKline had sponsored the Dream trial in an effort to expand the product beyond a treatment for diabetes by using it to prevent the disease.
In the Dream trial, patients taking Avandia had 66 percent more heart attacks, 39 percent more strokes and 20 percent more deaths from cardiovascular-related problems. That outcome, Dr. Nissen wrote, “virtually precludes the possibility of an overall benefit and suggest an unexpected mechanism for harm.”
Results from another trial, Adopt, published in December, also indicated an elevated risk of heart problems compared to another diabetes drug.
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